DNA viruses such as Herpes, Pox, Papillomavirus, Adenoviruses, Smallpox viruses, etc., can cause many different infectious diseases in humans. One example, Human papillomavirus (HPV), is a member of the papillomaviridae family of non-enveloped DNA viruses capable of infecting humans. Like all papillomaviruses, HPV is strictly epitheliotropic and establishes productive infections only in the stratified epithelium of the skin or mucous membranes. While the majority of the nearly 200 known types of HPV cause no symptoms in most people, some types can cause warts, while others can lead to various cancers, most notably cervical cancer.
More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with “high-risk” HPV types, different from the ones that cause skin warts, may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer; however, most infections with these types do not cause disease.
Most HPV infections in young females are temporary and have little long-term significance. 70% of infections are gone in 1 year and 90% in 2 years. However, when infection persists (in 5% to 10% of infected women), there is high risk of developing cervical precancer (lesions on the cervix), which can progress to invasive cervical cancer. This process usually takes 15-20 years, providing many opportunities for detection and treatment of the pre-cancerous condition, often with high cure rates.
While vaccination is an effective way to prevent HPV infection, therapeutic options are limited, expensive and often not well tolerated. Classical therapeutic approaches comprise cytodestructive and cytotoxic substances, surgical methods, laser and cryotherapy, possibly in combination with immunotherapy. In recent years, the acyclic nucleoside phosphonate cidofovir has proven to be effective in the treatment of a variety of clinical manifestations of several DNA viruses such as Herpes, Pox, Papillomavirus, Adenoviruses, Smallpox viruses, etc., in particular, cidofovir has been used to treat HPV-induced epithelial cell proliferation. In vitro treatment of HPV-positive cells with cidofovir has resulted in a concentration- and time-dependent inhibition of cell proliferation. Different parameters of apoptosis showed that the mechanism of cell death following treatment with cidofovir is based on apoptosis. Treatment with intravenous (systemic) cidofovir has been shown to result in the stabilization of disseminated papillomatosis. Local intratumor injections of cidofovir in patients with papillomatous lesions have been shown to result in a complete regression of the tumor. In addition, cidofovir topical gel has been successfully used for the treatment of severe, relapsing anogenital HPV lesions and cervical intraepithelial neoplasia. As cidofovir has been proven to be able to induce apoptosis, the regression of papillomatous tumors may be due, at least in part, to the induction of apoptosis by cidofovir.
As illustrated above, various formulations and routes of administration are presently used for the application of cidofovir. However, each application is presented with specific drawbacks. Systemic administration of an aqueous cidofovir solution, by intravenous injection, possibly leads to systemic side effects. Cidofovir concentrations need to be increased to assure adequate cidofovir amounts at the target site, which may result in nephrotoxicity. On the other hand, local injections of cidofovir at the target site may require multiple injections to assure adequate coverage of the target site. As an alternative to aqueous solutions of cidofovir for injection, creams, gels and films have been developed for topical applications, which may assure localized application to the target site. However, the stability of cidofovir in creams is low and its activity, therefore, deteriorates fast. In addition, the preparation of films includes a heating step, which may entail a risk of heat-mediated cidofovir degradation.